NEURAL SUBSTRATES OF AGE-RELATED COGNTIVE DECLINE IN MONKEYS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. (From parent Aging PPG at Boston University ¿ Longitudinal Study only conducted at NEPRC) The rhesus monkey is a model of normal human aging that enables cognitive testing to be followed by optimal preservation of brain tissue for multidisciplinary studies. The proposed studies test the hypothesis that age-related cognitive decline results from a cascade of mild degenerative changes beginning with inflammation in white matter followed by functional and then structural changes in neurons. We will study three cohorts of monkeys. The first cohort of 36 will be used in a cross-sectional study and will consist of subjects covering the adult life span from 5 to 30 years old. After behavioral testing, MRI scans will be followed by in vivo neurophysiology and a two stage perfusion to provide fresh and fixed tissue to identify brain changes underlying cognitive decline. A second cohort of 6 middle aged monkeys will proceed like cohort 1 except they will be fixed for electron microscopy to supplement existing samples and allow identification of the ultrastructural changes that appear first in middle age in relation to cognitive decline. A third cohort of 12 early middle aged monkeys (ages 13-15) will be followed longitudinally for 4+ years with repeated behavioral testing, MRI scans of the brain, and samples of blood and CSF. As the prevalence of cognitive impairment is low at 13 - 15 but high by 20, these data will allow us to identify the cognitive profile and rate of decline of individual monkeys. Longitudinal MRIs will reveal concurrent changes in brain morphology, and CSF and blood samples will allow biomarkers to be assessed. For cohorts 1 and 3, in vivo neurophysiological assessment of compound action potentials will be followed immediately by collection of unfixed samples from one hemisphere before the remainder of the brain is fixed.